The feasibility of transdermal delivery for a selected drug depends on the efficacious plasma concentration of the drug, the flux of the drug across skin, and the surface area of skin. For reasons of consumer acceptance, the practical surface area of a transdermal system is limited from approximately 5 to 100 cm.sup.2. With this limitation on surface area, the therapeutic transdermal administration of many drugs requires an increase in the inherent skin permeability. To this end, a large body of literature has developed concerning compounds which enhance percutaneous absorption.
The ability of water alone to increase skin permeation by hydration or occlusion has been well-documented over the past few decades. While it is published that ethanol can enhance skin permeation in certain instances, even this knowledge is not general in the literature. Two very recent review articles of skin permeation enhancers (B. W. Barry, "Penetration Enhancers in Skin Permeation", Proceedings of the 13th International Symposium on Controlled Release of Bioactive Materials, ed. by Chaudry & Thies, Controlled Release Society, Lincolnshire, Ill. 1986 pp 136-137 and Cooper & Berner, "Penetration Enhancers", in The Transdermal Delivery of Drugs, Vol. II ed. by Kydonieus and Berner, CRC Press, Boca Raton, Fla. 1986 pp. 57-62) fail to mention ethanol. In current literature, it is stated that ethanol is added in the estradiol transdermal system to solubilize the drug (Int. J. Pharmaceut. 32:159-163, 1986) and that ethanol does not increase the skin permeability to estradiol.
Although the role of ethanol is not generally recognized in the current art, many studies of ethanol and skin have been published. The established maximum skin permeation of ethanol is 400-800 mcg/cm.sup.2 /hr (Physiol. Rev. 51:702-747, 1971) and certainly no greater than 1300 mcg/cm.sup.2 /hr (U.S. Pat. No. 4,379,454). Ethanol is often included in topical formulations as a volatile excipient which evaporates to deposit the active ingredients on the skin, but does not alter skin permeability.
The use of ethanol to increase skin permeation in an estradiol transdermal system is based on a flux range for ethanol of 100-800 mcg/cm.sup.2 /hr and the finding that skin permeation from neat ethanol is as good or better than from aqueous ethanol donor solutions. U.S. Pat. No. 4,379,454 refers to this preferred flux range for ethanol and to a preferred membrane which is permeable to ethanol and estradiol, but not to other compounds in the system reservoir. The use of water from 50-75% at most in this reservoir is suggested to lower the solubility of estradiol, but there is no mention of a change in skin permeation due to the aqueous nature of the formulation. The commercial reduction to practice of this system utilizes a neat ethanol gel in the reservoir and a rate-limiting membrane which is permeable to ethanol in the range of 400 mcg/cm.sup.2 /hr and is relatively impermeable to water.
Recent studies of skin permeation of the effect of ethanol and aqueous ethanol on the flux of estradiol through hairless mouse skin, levonorgestrel through rat skin, and salicylic acid through human skin conclude that neat ethanol increases skin permeation better than aqueous ethanol.
The use of ethanol for increasing skin permeation of compounds which are ionized in aqueous solutions (including dipolar ions, i.e. zwitterions) at all practical pH values is not found in the literature.